Genetics & Syndromes Flashcards
What is the incidence of Down’s Syndrome?
What chromosomal defects results in the occurrence of Trisomy 21? (3)
1 in 650
Meiotic non-disjunction (94%)
Translocation (5%)
Mosaicism (1%)
What occurs in meiotic non-disjunction in Down’s syndrome?
Meiosis error separating csome21 → 1 gamete has 2 csome21s → fertilisation = 3
Can be maternal/paternal origin (incidence drastically increases in mums > 30)
What is the incidence risk of recurrent down’s syndrome in mums < 30 and >30
Mums < 30 → 1 in 200 recurrence risk
Mums > 30 → 1 in 650 (same as general pop)
What occurs in translocation in Down’s syndrome?
What is the incidence risk if the carrier is mum/dad?
Extra csome21 joined onto another (usually csome14)
Mum carrier → 10-15% risk
Dad carrier → 2.5% risk
If either parents carries 21:21 translocation → all children will be affected
What occurs in mosaicism in Down’s syndrome?
Chromosomally normal zygote (after meiosis) but non-disjunction at mitosis later during conception
→ Milder phenotype
What are the craniofacial features in Trisomy 21? (8)
Round face Upslanting epicanthic folds/palpebral fissures Flat occiput (+ 3rd fontanelle) Small mouth + protruding tongue Small/arched palate Small ears Flat nasal bridge Pigmented (Brushfield) spots in iris
What are some other (non-cranio-facial) congenital abnormalities seen in Trisomy 21? (7)
Short neck
Single palmar creases + incurved 5th finger
Sandal toe gap
Hypotonia
Congenital heart defects (30-40%)
Duodenal atresia
Hirschprung disease
What is the life expectancy / prognosis for Down’s syndrome?
Prognosis varies with learning disability
>85% live >1yr
>50% live >50yrs
What are the long-term medical problems associated with Down’s syndrome (12)
Delayed motor milestones
Mod-severe learning difficulties
Small stature
Hearing impairment (secretory otitis media) Visual impairment (cataracts, squint, myopia)
Susceptibility to infections Risk coeliac Risk hypothyroidism Risk leukaemia + solid tumours Risk atlanto-axial instability Risk Epilepsy Risk Alzheimer's
What Ix can be done for Trisomy 21? (4)
In utero Ix:
Biochemical markers
Nuchal translucency on USS
Amniocentesis
Blood test - karyotype using FISH (fluorescent in situ hybridisation)
What is the incidence of Turner Syndrome?
What chromosomal defects/events → it?
1 in 2500 (>95% early miscarriage - incompatible with males)
Only 1x - 45X (50% girls)
Short-arm deletion of an X
Mosaic form
What are the clinical features of Turner Syndrome (2 of which are characteristic + seen in all) (2+12)
- Shorter stature
- Ovarian dysgenesis → infertility
Widely spaced nipples
Wide carrying angle
Neck webbing / thick neck
Spoon-shaped nails
Lymphoedema of hands/feet (persists in neonates)
Congenital heart defects (Coarc of Ao, aortic valve probs)
Renal anomalies (horseshoe kidney)
Visual impairments (sclera, cornea, glaucoma)
Recurrent otitis media
Hypothyroidism
Delayed puberty
Osteoporosis (lack of oestrogen)
Normal intellectual function (autistic/ADHD features common)
What Ix can be done for Turner Syndrome? (2)
USS for fetal oedema of hands/feet or cystic lymphangioma
Amnio/CVS - karyotype
What long-term problems can occur in Turner Syndrome? (9)
Hypothyroidism
Heart murmur
Kidney + urinary tract probs
Lymphoedema
High BP DM GI bleeding Osteoporosis Scoliosis
What psychological problems can occur in Turner’s? (5)
LDs (rare) Attention + hyperactivity probs Spatial awareness probs Numeracy probs Infertility
What kinds of regular health checks need to be done in Turner’s syndrome patients? (5) - to prevent long-term complications
Bone density Hearing/ears Thyroid BP Glucose
What hormonal therapy can be given in Turner’s syndrome? (2) + at what ages
GH therapy - started age 5-6 until 15-16
Oestrogen+progesterone therapy age 12-15
What are some SEs of GH therapy (used in Turner’s)? (6)
Headaches Visual probs N+V Joint pain Insulin resistance Hypothyroidism
What different pathogenic mechanisms can occur → dysmorphic features in syndromes? (4)
Malformation (structural defect occurring during devel)
Deformation (intrauterine mechanical force)
Disruption (destruction of originally normal parts)
Dysplasia (abnorm cell structure/function)
What are the dysmorphic features seen in Noonan syndrome? (4)
Short big forehead + low hairline
Wide set eyes
Low set ears
Small jaw + short neck
What are the dysmorphic features seen in Williams syndrome? (4)
Wide set eyes
Upturned nose
Small chin
Puffy cheeks
What are the dysmorphic features seen in Prader-Willi syndrome? (4)
Narrow forehead at temple
Almond-shaped eyes
Narrow nasal bridge
Thin upper lip + downturned mouth
What is the incidence of Duchenne’s Muscular Dystrophy
What is it due to?
When do features first present?
1 in 4000 males
X-linked recessive (deletion on short arm of X)
Average age of Dx if 5.5yrs (but most symptomatic by 3yrs)
Describe the pathology behind Duchenne’s
No dystrophin protein coded for → which connects cytoskeleton of muscle fibre to ECM (extra-cell matrix)
Abnormal intracellular signalling pathway → Ca influx → Calmodulin breakdown → XS free radicals → Myofibre necrosis
What are the clinical features of Duchenne’s? (8)
Life expectancy = ?
Waddling gait
Gowers sign
Pseudohypertrophy of calves (mm fibres → fibrous)
Muscular atrophy progression → weakness + non-ambulant by 10-14yrs
Scoliosis is common complication
LDs (1/3rd)
Language delay
Life expectancy = 20s (resp failure/cardiomyopathy)
What Ix can be done for Duchenne’s Muscular Dystrophy? (6)
FH**
Bloods: creatine kinase (muscle breakdown)
Muscle biopsy (conclusion / determines type)
EMG of muscle
CT/MRI
CXR/ECHO (heart)
What are the general supportive / complication preventative managements in Duchenne’s? (5)
Corticosteroids in ambulant children - preserve mobility + prevent scoliosis
Appropriate exercises - preserve motility + prevent scoliosis
Good sitting posture - prevent scoliosis
Overnight CPAP/NIPPV (intercostal weakness = noctural hypoxics)
Heart condition - monitoring/treatment
What is the incidence / aetiology of Type 1 + 2 Neurofibromatosis?
NF1
1 in 3000
Autosominal dominant (but 1/3rd new mutations)
NF2 (involves CNS too)
1 in 25000
Autosomal dominant (both are highly penetrant)
What are the diagnostic criteria for NF-1? (7)
1+ neurofibroma 1st degree relative with NF1 6+ cafe au lait spots (>5mm b4 puberty; >15mm after) Axillary freckles Optic glioma (visual impairment) Bony sphenoid lesion (eye protrusion) Lisch nodule (iris haematoma)
What are the diagnostic criteria for NF-2? (4)
Bilateral vestibular schwannomas (CN8 masses)
1st degree with NF2
AND
Unilateral CN8 mass OR any 2 of: meningioma, schwannoma, glioma, neurofibroma, juvenile cataracts
Multiple meningiomas
AND
Unilateral CN8 mass OR any 2 of: meningioma, schwannoma, glioma, neurofibroma, juvenile cataracts
Unilateral CN8 mass AND any 2 of: meningioma, schwannoma, glioma, neurofibroma, juvenile cataracts (posterior subcapsular lenticular opacities)
What other (systemic) effects can occur with NF-1? (7)
LDs (60% - mild)
Small + underweight
Scoliosis
Brain/CNS: Migraine, Epilepsy, personality change
What CNS + Facial symptoms can occur in NF-2?
Brain: headache, seizures, disturbed vision, vomiting
Spine: back pain, muscle weakness
Facial: numb/weak face, facial pain
What are the major (7) + minor (8) Dx criteria for Tuberous Sclerosis?
Need 2 major OR 1 major 2 minors Major: Facial angiofibromas 3+ ash-leaf spots (hypomelanotic macules) Shagreen patch (connective tissue naevus) (lumbar spine) Cortical tuber (brain lesions) Cardiac rhabdomyoma Retinal hamartoma Renal angiomyolipoma
Minor: Dental enamel pits Gingival fibromas Bone cysts Hamartomatous rectal polyps Non-renal hamartoma Polycystic kidneys Skin tags FH
What is the incidence of tuberous sclerosis / aetiology?
How does it typically present?
1 in 9000
Dominant inherited disorder but 70% new mutations
Typically presents in childhood with skin changes + epilepsy <5yrs
What are the neurological features of tuberous sclerosis? (3)
Epilepsy - often focal
Infantile spasms - devel delay
Intellectual impairment
What is achondroplasia?
What are some general features? (4)
What are some of the long-term complications? (4)
Inherited autosomal dominant (50% new mutations) → short limb dwarfism
Short stature + limbs
Macro/hydrocephalus
Cranio-facial (frontal bossing + nasal bridge depression)
Lumbar lordosis
Resp e.g. apnoea
Spinal canal stenosis → neuro probs
Early OA + kyphosis
Obesity
What is Phenylketonuria (PKU)?
What is the general management
Rare congenital disorder where body cannot breakdown phenylalanine → accumulation in body
Left untreated → severe LDs (would not surpass capability of a 1-2y/o)
Tx: dietary (low prot, avoid aspartame, supplements)
What are the 3 main features of Fetal alcohol syndrome?
Cranio-facial (esp mid-facial) abns
IUGR + failure to thrive
Cognitive impairment, LDs + impulsiveness
What is Rett’s syndrome?
What is the incidence
What are the different stages of the disease?
Genetic (non-inherited) pervasive development disorder (sim to Autism)
Incidence 1 in 20,000 (almost always girls)
Developmental arrest
Developmental regression (rapid)
Stationary phase (motor/intellectual impairment but social/communication improvements)
Late motor deterioration - by 10y/o, quadriparesis
What is Fragile X syndrome?
Incidence
What are the main features? (2)
Faulty X sequences → faulty neural development
1 in 4000 males + 1 in 8000 females
Craniofacial (large ears, long face)
Autistic-like / ADHD / mental retardation
What is Marfan’s syndrome?
Incidence
Autosomal dominant condition of connective tissue
Incidence 2-3 in 10,000 (girls 1 : 1 boys)
What are some of the characteristic features of Marfan’s? (4)
Tall + thin + kyphoscoliosis
CV: thoracic dissection, AAA, dysrhythmia, murmur
Eyes - lens dislocation, glaucoma
Joints - arthralgia
What are the 3 key features of Noonan’s?
Short stature
Distinctive facial features
Congenital heart disease (varied severity)
